WO2010103291A2 - Traitement de maladies associées à l'hyperactivité du système du complément - Google Patents

Traitement de maladies associées à l'hyperactivité du système du complément Download PDF

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WO2010103291A2
WO2010103291A2 PCT/GB2010/000465 GB2010000465W WO2010103291A2 WO 2010103291 A2 WO2010103291 A2 WO 2010103291A2 GB 2010000465 W GB2010000465 W GB 2010000465W WO 2010103291 A2 WO2010103291 A2 WO 2010103291A2
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factor
subject
ic3b
disease
inactivating
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PCT/GB2010/000465
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WO2010103291A3 (fr
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Peter Lachmann
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Cambridge Enterprise Limited
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Priority to EP17206534.4A priority Critical patent/EP3363454B1/fr
Priority to AU2010222710A priority patent/AU2010222710A1/en
Priority to CN2010800193697A priority patent/CN102413836A/zh
Priority to US13/256,311 priority patent/US9066941B2/en
Priority to EP10710391A priority patent/EP2405931A2/fr
Priority to CA2755473A priority patent/CA2755473C/fr
Publication of WO2010103291A2 publication Critical patent/WO2010103291A2/fr
Publication of WO2010103291A3 publication Critical patent/WO2010103291A3/fr
Priority to US14/753,193 priority patent/US9782460B2/en
Priority to US15/720,933 priority patent/US10940186B2/en
Priority to US17/171,524 priority patent/US20210268076A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)

Definitions

  • This invention relates to agents, compositions and methods for the prevention, treatment, or amelioration of diseases in which the underlying pathology is linked to overactivity of the C3b-feedback cycle and the generation and pro-inflammatory effects of iC3b, a product of the activation of the complement system.
  • the complement system comprises a set of about 30 proteins which may be located in the fluid phase (generally, in plasma) or on the surfaces of cells in which the proteins are expressed.
  • the system serves several important biological functions related to both innate and adaptive immunity and is phylogenetically ancient. It must recognize foreign (non-self) entities, react to them in a highly amplifiable way in order to trigger an effective defensive biological response and yet keep the system under tight control to avoid collateral ("self) damage.
  • the components may be grouped into eight functional classes:
  • Recognition molecules which bind to pathogen-associated molecular patterns not found in the host organism (e.g. bacterial carbohydrate) or to antigens defined through previous encounter or as part of the pre-existing immunoglobulin repertoire.
  • pathogen-associated molecular patterns e.g. bacterial carbohydrate
  • antigens defined through previous encounter or as part of the pre-existing immunoglobulin repertoire.
  • An example is Mannan-binding lectin (MBL).
  • Amplifiers of the activation processes either enzymatic (Factor D) or non-enzymatic (Properdin)
  • Soluble negative regulators either enzymatic (Factor I) or non-enzymatic (e.g. Factor H, C4bp)
  • Negative regulators located on the surfaces of cells which they protect against attack by the endogenous complement system e.g. CRl 3 DAF, MCP,CD59
  • Receptors which permit cellular signaling by products of complement activation, thus linking the process to other immune and cell regulatory functions e.g. CR2, CR3, C3a, C5a receptor.
  • the archaeo-complement system probably consisted of a form of the C3 protein alone - this was cleaved by microbial proteases into C3a and C3b.
  • the small C3a fragment is a chemotactic factor.
  • the large fragment, C3b acquires briefly the capacity to attach covalently to the microbe following cleavage of its thiol ester group. Bound C3b acts as an "opsonisation marker" marking the microbe for destruction by phagocytic cells.
  • the complement system achieved a primary level of amplification through addition of the protease Factor B which mediates positive feedback by combining with the C3b product to form a complex, C3bB which after cleavage by microbial or other proteases forms a convertase, C3bBb, capable of activating more C3.
  • the corresponding control system to prevent excessive C3b generation in higher vertebrates with pumped blood circulation was provided by a soluble plasma protease (FI) which catalyses the cleavage of C3b to iC3b (the "First clip”).
  • FI soluble plasma protease
  • Factor I will cleave C3b only when this is complexed to a molecule with "Factor I cofactor activity”.
  • Factor H the principal molecule with this property is Factor H.
  • iC3b cannot participate in convertase formation and hence amplification but it can function as a powerful pro-inflammatory agent through interaction with complement receptor type 3 (CR3, CDl lb/CD18) an integral membrane protein found on neutrophils and monocytes which engages iC3b, a reaction enhanced by also binding microbial carbohydrate (e.g. beta glucan, (Xia Y, Vetvicka V, Yan J, Hanikyrov ⁇ M, Mayadas T, Ross GD (1999) The beta-glucan-binding lectin site of mouse CR3 (CD11NCD18) and its function in generating a primed state of the receptor that mediates cytotoxic activation in response to iC3b-opsonized target cells. J Immunol, 162 (4): 2281-90).
  • microbial carbohydrate e.g. beta glucan, (Xia Y, Vetvicka V, Yan J, Hanikyrov ⁇ M, Mayadas T, Ross GD (1999)
  • iC3b can be further broken down by Factor I (FI) and the membrane-bound cofactor CRl (CD35) in a so-called “Second clip" which yields C3d,g - a C3 fragment which is not pro-inflammatory (it does, however, have an effect on the adaptive immune system through stimulation of specific antibody production through interaction with CR2) and C3c.
  • FI Factor I
  • CD35 membrane-bound cofactor
  • FIG. 1 This shows an outline of the activation of the complement system initiated by recognition events at the beginning of the pathways and amplified by the C3b amplification loop — the generation and deactivation of iC3b.
  • the C3b amplification loop is also shown in Figure 2.
  • This amplification loop is a balance between two competing cycles both acting on C3b: the C3 feedback cycle which enhances amplification, and the C3 breakdown cycle which down-regulates it. It is solely the balance between their rates of reaction on which amplification depends.
  • the C3 breakdown cycle generates iC3b as its primary reaction product.
  • iC3b through its reaction with the leukocyte integrins (and complement receptors) CR3 (CDl lb/CD18) and CR4 (CDl lc/CD18) is the most important mechanism by which complement mediates inflammation.
  • the invention derives from the understanding that the genetic predisposing factors for several inflammatory diseases all serve to enhance the activity of the C3b feedback cycle thereby creating a pro-inflammatory phenotype of which the formation of iC3b and its reaction with CR3 is a critical component.
  • a method of preventing, treating, or ameliorating a disease associated with overactivity of the complement C3b feedback cycle which comprises increasing the level of C3b-inactivating and iC3b-degradation activity in a subject to a level that exceeds a normal level of C3b-inactivating and iC3b-degradation activity.
  • an agent or agents with C3b-inactivating and iC3b-degradation activity for use as a medicament.
  • an agent or agents with C3b-inactivating and iC3b-degradation activity for use in the prevention, treatment, or amelioration of a disease associated with overactivity of the complement C3b feedback cycle, at a dosage that increases the level of C3b-inactivating and iC3b-degradation activity in a subject to a level that exceeds a normal level of C3b-inactivating and iC3b-degradation activity.
  • an agent or agents with C3b- inactivating and iC3b-degradation activity in the manufacture of a medicament for the prevention, treatment, or amelioration of a disease associated with overactivity of the complement C3b feedback cycle, at a dosage that increases the level of C3b-inactivating and iC3b-degradation activity in a subject to a level that exceeds a normal level of C3b-inactivating and iC3b-degradation activity.
  • complement C3b feedback cycle is used herein to refer to a positive feedback cycle acting through C3b (the major product of C3 cleavage), which interacts with factors B and D of the alternative pathway to form a C3 -cleaving enzyme.
  • “Overactivity of the complement C3b feedback cycle” means that there is increased formation of the C3-cleaving enzyme compared with a normal subject, with consequent increased turnover of C3 and components of the alternative pathway.
  • the turn-over of C3 can be measured in-vivo using 125 I-labelled C3.
  • turn-over of C3 can be measured indirectly in-vitro by determining the rate of C3 conversion to iC3b when a small complement activating stimulus is given (as described in Lachmann PJ and Halbwachs L (1975) The influence ofC3b inactivator (KAF) concentration on the ability of serum to support complement activation. CHn Exp Immunol 21 109).
  • the disease is associated with an ongoing predisposition to overactivity of the C3b feedback cycle.
  • This is distinguished over diseases in which there may be a temporary susceptibility to overactivity of the C3b feedback cycle, for example during a particular phase of the disease.
  • Factor I and Factor H have been reported to be decreased in the pre or early phases of the exacerbation stage, but not during most of the regression stage of systemic lupus erythematosus (SLE).
  • the disease is an inflammatory disease.
  • the disease is not an autoimmune disease, especially SLE, rheumatoid arthritis or glomerulonephritis .
  • AMD Age-related Macular Degeneration
  • aHUS atypical haemolytic uraemic syndrome
  • MPGN2 membranoproliferative glomerulonephritis Type 2
  • atherosclerosis in particular, accelerated atherosclerosis
  • chronic cardiovascular disease and Alzheimer's disease (particularly Alzheimer's disease in a subject carrying an ApoE4 allele, i.e. a subject who is heterozygous or homozygous for the ApoE4 allele).
  • methods of the invention may further comprise determining whether the subject has a genetic predisposition to the disease or a family history of the disease, and administering appropriate prophylaxis or therapy depending on the result of the determination.
  • Examples of genetic predispositions to diseases associated with overactivity of the complement C3b feedback cycle are: a mutation in Factor H that reduces its ability to function as a Factor I cofactor compared with wild-type Factor H; a mutation in Factor H that reduces its binding to C3b compared with wild-type Factor H; homozygous Factor H deficiency; a mutation in membrane cofactor protein (MCP) that reduces its function compared with wild-type MCP; heterozygous Factor I deficiency; a gain-of-function mutation in Factor B; or a C3F allotype.
  • MCP membrane cofactor protein
  • All the predisposing alleles share the property of enhancing the activity of the C3b amplification loop by either upregulating the C3b feedback cycle or downregulating the C3b breakdown cycle. They all therefore promote a hyperinflammatory complement phenotype. This will produce its effects by increasing the production of C5a and of the membrane attack complex and, most importantly, by the increased production of iC3b which through its reaction with CR3 (CD 11 b/CD 18) and CR4 (CD 11 c/CD 18) on neutrophils, monocytes and NK cells provides complement's most powerful pro-inflammatory mechanism.
  • agent with C3b-inactivating and iC3b-degradation activity is used herein to mean an agent with serine protease activity that is able to catalyse the cleavage of C3b to iC3b (the “First Clip") and degradation of iC3b (the “Second Clip”).
  • the agent may require one or more cofactors in order to catalyse these reactions. For example, Factor H may be required for the First Clip, and CRl may be required for the Second Clip.
  • a preferred example of the agent is Factor I.
  • Factor I may alternatively be used, such as fragments or derivatives of Factor I that retain C3b- inactivating and iC3b-degradation activity.
  • the Factor I, or fragment or derivative may be plasma-derived Factor I, or recombinant Factor I, or fragment or derivative.
  • the Factor I is of the same species as the subject.
  • derivatives of Factor I that retain C3b-inactivating and iC3b-degradation activity may be prepared by providing a protein comprising a sequence that differs from native Factor I sequence by one or more conservative amino acid substitutions, and/or by deletion of one or more amino acid residues.
  • such Factor I derivatives retain at least 60% amino acid identity across the entire length of the sequence with native Factor I. More preferably a Factor I derivative retains at least 70%, 80%, 90%, or 95% amino acid identity across the entire length of the sequence with native Factor I.
  • the agent could be provided in a form which requires modification (for example prior to administration, or in vivo) to provide the C3b-inactivating and iC3b-degradation activity. It is also envisaged that the C3b-inactivating and iC3b-degradation activity could each be provided by separate agents, which may be administered together or separately (for example, sequentially).
  • agents with C3b-inactivating and iC3b-degradation activity may be administered.
  • the agent(s) is(are) not administered with Factor H.
  • the subject has a normal level of C3b-inactivating and iC3b-degradation activity provided by the subject's Factor I.
  • a normal level is regarded to be in the range 30-40 ⁇ g/ml Factor I in the subject's plasma.
  • Measurement of plasma Factor I can be determined using conventional methods, for example antigenically, using radial immunodiffusion, "rocket” electrophoresis, or nephelometry or functionally, using conglutinin (Lachmann & Muller-Eberhard, 1968, J Immunol. 100, 691), or a haemolytic inhibition assay (Lachmann, Nicol and Aston, 1973, Immunochem 10 695).
  • the level of C3b-inactivating and iC3b-degradation activity in the subject's plasma is increased by at least 10% above the normal level, preferably for a period of at least one to two weeks.
  • the level of activity in the subject's plasma is increased by no more than 50%, preferably no more than 25% above the normal level.
  • the level of activity is increased by administering an agent(s) with C3b-inactivating and iC3b-degradation activity to the subject.
  • the agent is preferably used at a dosage for increasing the level of activity in the subject's plasma by at least 10% above the normal level, preferably for a period of at least one to two weeks.
  • the dosage increases the level of activity in the subject's plasma by no more than 50%, preferably no more than 25% above the normal level.
  • the agent (preferably Factor I) is preferably used at a dosage up to 20mg/kg, for example 0.001 or 0.05mg/kg to 20mg/kg, more preferably less than 6mg/kg, for example 0.001 or 0.05mg/kg to less than 6mg/kg, more preferably up to 1.5mg/kg, for example 0.001, 0.05, or 0.2mg/kg to 1.5mg/kg or 0.001, 0.05, or 0.2mg/kg to lmg/kg, or less than lmg/kg, for example 0.001, 0.05, or 0.2mg/kg to less than lmg/kg.
  • Preferred doses for human subjects are up to 250mg, for example 6.5 or lOmg to 250mg, preferably less than 50mg, for example from 6.5 or lOmg to less than 50mg, or 10-20mg.
  • the agent may preferably be administered at a dosage up to 250mg, for example from 6.5 or lOmg to 250mg, preferably from 6.5 or lOmg to less than 50mg, for example 10-20mg.
  • the agent may preferably be administered at a dosage of 0.05 to 20mg/kg, for example 0.05 to less than 6mg/kg, or 0.05 to less than lmg/kg.
  • the agent may be administered a dosage of 0.001 to lmg/eye Factor I.
  • the level of activity may be increased by administering C3b-inactivating and iC3b-degradation activity at least once per month, or at least once per day.
  • C3b-inactivating and iC3b-degradation activity will depend on many factors, including the route of administration, the type of disease and the severity, stage of the disease, the plasma half life of the C3b-inactivating and iC3b-degradation activity in the preparation (the plasma half life of Factor I is believed to be approximately one week), the background factor I levels in the patient, the desired steady-state protein concentration level, the influence of any therapeutic agents used in combination with the treatment method of the invention, the age, health, and sex of the subject. In many cases, it will be appropriate to monitor progress of the disease to determine the effect of the treatment, and based on the results determine whether or not treatment should be continued, and the appropriate frequency of the treatment.
  • aHUS atypical haemolytic uraemic syndrome
  • C3b- inactivating and iC3b-degradation activity is preferably administered if the subject is determined to be suffering from an infection or a fever.
  • Progress of the aHUS may be monitored by the blood platelet count, the presence of red cell fragments in the blood, the presence of raised levels of lactate dehydrogenase (LDH) in the blood, or the concentration of urea or creatinine in the blood, and/or by the enumeration in urine of red blood cells, white blood cells, and casts and measurement of urinary protein.
  • LDH lactate dehydrogenase
  • C3b- inactivating and iC3b-degradation activity is preferably administered every 2 to 4 weeks.
  • Progress of AMD may be monitored by determining the extent of drusen formation (deposits that accumulate beneath the retinal pigmented epithelium). If the extent of drusen formation is reduced, or if the rate of drusen formation is reduced by the treatment, then the frequency of administration of the C3b-inactivating and iC3b-degradation activity may also be reduced.
  • the progress of AMD may be monitored by measuring in vivo the amount of C3 fragments bound in the retina.
  • a binding agent that binds to iC3b but not to C3 or C3b.
  • the binding agent is a monoclonal antibody or a fragment or derivative thereof that retains binding specificity for iC3b.
  • the monoclonal antibody or fragment or derivative should not induce an adverse immune reaction in the subject to whom it is administered.
  • a monoclonal antibody that binds iC3b (but not native C3 or C3b) is described in Lachmann et al. (Immunology, 1980, 41(3): 503-515 - Clone 9).
  • This antibody is available commercially from Hycult Biotechnology b.v. (Catalog no. HM2199, Monoclonal antibody to human C3g, clone 9, also known as YB2/90-5-20; the antibody recognizes iC3b, C3dg and C3g in plasma, but does not recognize C3 or C3b).
  • a single chain Fv derived from YB2/90-5-20 may be used as a suitable binding agent for administration to a human subject.
  • the binding agent should be labeled so that it can be detected.
  • the binding agent is labeled with fluorescein. After intravenous injection this will stain deposits in the eye which can then be quantitated by fluorography.
  • binding agents that bind to iC3b, but not to C3 or C3b may be used for the diagnosis of an inflammatory lesion in the eye, for example as a result of Age-related Macular Degeneration (AMD).
  • AMD Age-related Macular Degeneration
  • a method for diagnosing whether a subject has an inflammatory lesion in an eye which comprises administering a binding agent that binds to iC3b, but not to C3 or C3b, to the subject, and determining whether the binding agent binds to the retina in the eye of the subject.
  • Presence of binding agent bound at the retina in the eye of the subject indicates that the subject has an inflammatory lesion in that eye.
  • a method for monitoring progression of an inflammatory lesion in an eye of a subject which comprises administering to the subject a binding agent that binds to iC3b, but not to C3 or C3b, at a first point in time and at a subsequent second point in time, and determining the amount of binding agent that binds to the retina in an eye of the subject at the second point in time relative to the first point in time.
  • An increase in the amount of binding agent that binds to the retina at the second point in time relative to the first point in time indicates that the inflammatory lesion has progressed in the subject.
  • No change in the amount of binding agent that binds to the retina at the second point in time relative to the first point in time indicates that the inflammatory lesion has not progressed in the subject.
  • a decrease in the amount of binding agent that binds to the retina at the second point in time relative to the first point in time indicates that the inflammatory lesion has regressed in the subject. It will be appreciated that methods of the invention for monitoring progression of an inflammatory lesion may be used to determine the effectiveness of treatment of the inflammatory lesion in the subject.
  • binding agent that binds to iC3b, but not to C3 or C3b, to diagnose an inflammatory lesion in an eye of a subject, or to monitor the progression of an inflammatory lesion in an eye of a subject.
  • the invention further provides a kit for diagnosing whether a subject has an inflammatory lesion, or for monitoring the progression of an inflammatory lesion, in an eye of the subject, which comprises a binding agent that binds to iC3b, but not to C3 or C3b, and instructions for diagnosing whether the subject has an inflammatory lesion, or for monitoring the progression of an inflammatory lesion, in an eye of the subject using the binding agent.
  • the instructions may describe administration of the binding agent to the subject and/or how to determine whether the binding agent binds to the retina in an eye of the subject.
  • the binding agent may be labeled with a label that allows detection of the binding agent at the retina.
  • a suitable label is a fluorescent label, for example a fluorophore such as fluorescein.
  • the binding agent may be administered systemically, preferably intravenously, to the subject.
  • composition comprising a binding agent that binds to iC3b, but not to C3 or C3b, together with a pharmaceutically acceptable carrier, excipient, or diluents.
  • the composition is preferably suitable for systemic, preferably intravenous administration.
  • the binding agent is preferably a monoclonal antibody or a fragment or derivative of a monoclonal antibody.
  • a fragment or derivative of a monoclonal antibody that binds to iC3b, but not to C3 or C3b.
  • the derivative is a single chain Fv (scFv), for example an scFv of YB2/90-5-20.
  • the fragment or derivative is labeled, suitably with a fluorescent label, for example a fluorophore such as fluorescein.
  • Such fragments or derivatives may be used as binding agents in methods or kits of the invention for the diagnosis of an inflammatory lesion, or for monitoring the progression of an inflammatory lesion, in an eye of a subject.
  • Methods and kits of the invention for the diagnosis of an inflammatory lesion, or for monitoring the progression of an inflammatory lesion, in an eye of a subject may be used for the diagnosis of AMD, or for monitoring the progression of AMD, in the subject.
  • the subject is a human subject. However, it may alternatively be desired to ameliorate, treat, or prevent (or diagnose or monitor progression of) the disease in non-human animals, such as domestic pets.
  • a unit dose comprising an agent or agents with C3b-inactivating and iC3b-degradation activity for administration to a subject.
  • compositions in unit dose form which comprises an agent or agents with C3b-inactivating and iC3b-degradation activity, and a pharmaceutically acceptable carrier, excipient, or diluent for administration to a subject.
  • composition which comprises an agent or agents with C3b-inactivating and iC3b-degradation activity, and a pharmaceutically acceptable carrier, excipient, or diluent for administration to a subject.
  • a unit dose for, or adapted for intraocular administration which comprises an agent or agents with C3b-inactivating and iC3b-degradation activity.
  • a pharmaceutical composition preferably in unit dose form, for or adapted for intraocular administration, which comprises an agent or agents with C3b-inactivating and iC3b-degradation activity, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • unit dose for, or adapted for systemic administration which comprises an agent or agents with C3b-inactivating and iC3b-degradation activity.
  • the unit dose for, or adapted for systemic administration should be sterile, and free of pyrogens and viruses.
  • compositions preferably in unit dose form, for or adapted for systemic administration, which comprises an agent or agents with C3b-inactivating and iC3b-degradation activity, and a pharmaceutically acceptable carrier, excipient, or diluent.
  • Systemic administration is preferably intravenous or intramuscular administration.
  • a unit dose or composition of the invention may comprise up to 250mg, for example from 1 or lOmg to 250mg, preferably less than 50mg, for example from 1 or lOmg to less than 50mg, preferably 10-20mg, of an agent or agents with C3b-inactivating and iC3b-degradation activity.
  • a unit dose or composition of the invention for, or adapted for, administration to a human subject.
  • a unit dose or composition of the invention may be in solid form, preferably lyophilised form.
  • the agent of the unit dose or composition of the invention is Factor I, or a fragment or derivative of Factor I that retains C3b-inactivating and iC3b-degradation activity.
  • the Factor I, or. fragment or derivative may be plasma-derived Factor I, or recombinant Factor I, or fragment or derivative.
  • Figure 1 shows an outline of the activation of the complement system initiated by recognition events at the beginning of the pathways and amplified by the C3b amplification loop — the generation and deactivation of iC3b and the dependence of those events on Factor I, Factor I cofactors and Factor H is noted;
  • Figure 2 shows the C3b amplification loop, which is a balance between two separate and competing pathways - the C3b feedback cycle and the C3b breakdown cycle;
  • Figure 3 shows the effect of increased factor I (FI) concentration on C3 conversion by inulin and by aggregated IgG.
  • the invention provides for a therapy which by raising Factor I concentration reduces the activity of the C3b-feedback cycle.
  • Heterozygous deficiency of Factor I is associated with aHUS (Kavanagh D, Richards A, Noris M, Hauhart R, Liszewski MK, Karpman D, Goodship JA, Fremeaux-Bacchi V, Remuzzi G, Goodship TH, Atkinson JP. (2008) Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome.
  • CFI complement factor I
  • Gain-of-function mutations in complement factor B are associated with atypical haemolytic uraemic syndrome.
  • the C3F allotype is associated with an increased risk of AMD (Yates JR, Sepp T, Matharu BK, Khan JC Thurlbv DA, Shahid H, Clayton DG, Hayward C, Morsan J. WrishtAF, Armbrecht AM, Dhillon B, Deary IJ, Redmond E, Bird AC, Moore AT, 2007 Complement C3 variant and the risk of age-related macular degeneration N Engl J Med. ,357:553-61).
  • C3F carries an increased risk of atherosclerotic vascular disease (Sorensen H 1 Pissing J (1975) Association between the C3F gene and atherosclerotic vascular diseases. Hum Hered. :25(4):279-83. )
  • C3F augments the C3b-feedback cycle by forming a more active C3-convertase (Harris C and Morgan BP personal communication)
  • mice membranoproliferative glomerulonephritis Type 2 (MPGN2, a renal inflammatory condition), occurs spontaneously in Factor H knockout (k/o) mice and results in consumption of C3, and iC3b deposition in glomeruli. If such k/o mice are then made to express a mutant form of FH functionally equivalent to the FH mutant associated with aHUS in man, they develop aHUS but not MPGN2 (Pickerins MC, de Jorse EG, Martinez-Bar ⁇ carte R, Recalde S, Garcia-Layana A, Rose KL, Moss J, Walvort MJ, Cook HT, de Cordoba SR. Botto M.
  • FI knockout mice do not show C3b deposition on their glomeruli despite having all their plasma C3 converted to C3b because of unrestrained action of the C3b-feedback cycle. Mice with both FI and Factor H deficiency also do not develop MPGN2. However injection of FI into the double k/o animals restores the MPGN2 pattern of C3 deposition in the glomeruli. This experiment demonstrates conclusively that conversion of C3b to iC3b is absolutely required for the development of the inflammatory renal disease (Rose KL, Paixao-Cavalcante D.
  • AMD 5 Complement and Alzheimer's Disease the possibility that there might be some association between AMD and Alzheimer's disease was raised by Dentchev et al. [Dentchev, T., Milam, A. H., Lee, V. M., Trojanowski, J. Q., and Dunaief, J. L. (2003). Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas. MoI. Vis. 9, 184-190] who reported that ⁇ amyloid protein could be found in the drusen from some AMD retinas but was not found in drusen from normal retinas.
  • Amyloid- ⁇ up-regulates complement Factor B in retinal pigment epithelial cells through cytokines released from recruited macrophages/microglia: another mechanism of complement activation in age-related macular degeneration. J. CeI. Physiol. 220, 119-128] that ⁇ amyloid also upregulates the production of Factor B in retinal pigment epithelium cells. It apparently does this by recruiting microglia which then produce cytokines that increase the production of Factor B. This would again produce a local hyperinflammatory state by increasing the activity of theC3b feedback cycle.
  • the Factor I strategy is also more attractive because the plasma concentrations of FI are relatively low (equivalent to about 35mg/litre in man) whereas addition of exogenous Factor H would require at least 10 times as much protein.
  • Pharmacological inhibition of Factor D has been attempted (e.g. Glover GI et al, MoI Immunol. 1988,25:1261-7) and compounds based on 3,4 dichloroisocoumarin or isatoic anhydride were found to be effective inhibitors of the enzyme but with insufficient selectivity to be viable drugs, (e.g. Jing Het al, JMoI Biol. 1998;282: 1061-81).
  • the present invention is therefore based on the therapeutic use of recombinant or plasma- derived FI.
  • Early studies on addition of exogenous FI in experimental systems suggested that supplementation probably needed to increase blood levels by no more than 25% (Lachmann & Halbwachs (1975). Based on the gene association studies noted above, it is likely that a chronic increase in FI plasma concentration of perhaps as little as 10% could have therapeutic effects if other mechanistic conditions were met.
  • the factor I materials of the present invention may be formulated into pharmaceutical compositions comprising a carrier suitable for the desired delivery method.
  • Suitable carriers include any material which when combined with this protein retains the function of the protein and is non-reactive with the subject's immune systems. Examples include any of a number of standard pharmaceutical carriers such as sterile phosphate buffered saline solutions, bacteriostatic water, and the like (see, generally, Remington: The Science and Practice of Pharmacy. ,2005 (21st Edition, Popovich, N (eds), Advanced Concepts Institute, University of the Sciences in Philadelphia, Philadelphia, PA.).
  • One or more human factor I formulations may be administered via any route capable of delivering the protein to the disease site.
  • Routes of administration include, but are not limited to, intravenous, intraocular, intraperitoneal, intramuscular, intradermal and the like.
  • Factor I preparations may be lyophilized and stored as a sterile powder, preferably under vacuum, and then reconstituted in bacteriostatic water containing, for example, benzyl alcohol preservative, or in sterile water prior to injection.
  • Treatment will generally involve the repeated administration of the protein preparation via an acceptable route of administration such as intravenous (IV) or intraocular (IO) injection at an effective dose.
  • IV intravenous
  • IO intraocular
  • Dosages will depend upon various factors generally appreciated by those of skill in the art, including the route of administration, the type of disease and the severity, stage of the disease, the plasma half life of the protein in the preparation (the plasma half life of Factor I is believed to be approximately one week), the background factor I levels in the patient, the desired steady-state protein concentration level, and the influence of any therapeutic agents used in combination with the treatment method of the invention.
  • a typical normal plasma concentration of Factor I in man is about 35 micrograms/ml. Allowing an extracellular fluid volume of about 10 litres gives a total of 350 mg Factor I. To raise this acutely by 10% would take 35mg; to raise it by 25% would take 88mg. Preferred amounts of Factor I are upto three times this amount, for example, upto 100-250mg every 1-3 weeks.
  • doses are likely to range from about 0.05 to 20 mg/kg with a frequency of dosing between daily and monthly as repeated administrations may be required to achieve disease inhibition or regression.
  • IO administration will involve significantly lower doses in the likely range of 1 to 1000 micrograms/eye.
  • a determining factor in defining the appropriate dose is the amount of a particular preparation necessary to be therapeutically effective in a particular disease context and this can only be determined by clinical investigation.
  • Patients may be evaluated for plasma factor I levels during therapy in order to assist in the determination of the most effective dosing regimen and related factors.
  • Conventional assay methods based on breakdown of C3b or C4b in the presence of a cofactor may be used for quantifying circulating factor I in patients prior to or during treatment.
  • Inulin - a standard suspension (50 mg/ml) in saline was sonicated. Dilutions of this suspension were made, the final concentration of inulin in the serum being given for each experiment.
  • Factor I - functionally purified FI was prepared from the euglobulin fraction of serum by
  • the titre of the purified FI standard solution was measured and compared to the normal serum titre by its capacity of inducing EAC 143 agglutination in presence of bovine conglutinin (Lachmann, & Muller-Eberhard, 1968). Variations in FI concentration in normal human serum were obtained by adding different dilutions of the purified FI standard solution to the serum.
  • FI Effect of increased FI concentration on complement activation by inulin (Fig. 3) FI inhibits C3 conversion by inulin at all concentrations of inulin used. It also inhibits factor B conversion by inulin. Quite small amounts of FI are sufficient for this inhibitory effect: an increase of only 15% of the normal FI concentration in the serum results in 50% inhibition of C3 conversion by inulin.

Abstract

Cette invention concerne l'accroissement du taux du facteur 1 à des valeurs dépassant les valeurs physiologiques pour traiter des maladies où la pathologie sous-jacente est associée avec la suractivité du cycle de régulation des fragments C3b et la production et les effets pro-inflammatoires du fragment iC3b. L'invention concerne également des méthodes, des agents et des compositions utilisés dans le traitement de ces maladies.
PCT/GB2010/000465 2009-03-13 2010-03-12 Traitement de maladies associées à l'hyperactivité du système du complément WO2010103291A2 (fr)

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EP17206534.4A EP3363454B1 (fr) 2009-03-13 2010-03-12 Traitement de maladies liées à une hyperactivité du système de complément
AU2010222710A AU2010222710A1 (en) 2009-03-13 2010-03-12 Use of Factor I for treating diseases involving the complement C3b feedback cycle
CN2010800193697A CN102413836A (zh) 2009-03-13 2010-03-12 与补体系统活性过高有关的疾病的治疗
US13/256,311 US9066941B2 (en) 2009-03-13 2010-03-12 Treatment of diseases related to hyperactivity of the complement system
EP10710391A EP2405931A2 (fr) 2009-03-13 2010-03-12 Traitement de maladies associées à l'hyperactivité du système du complément
CA2755473A CA2755473C (fr) 2009-03-13 2010-03-12 Utilisation du facteur complementaire i destine au traitement de maladies associees a l'hyperactivite du systeme complementaire
US14/753,193 US9782460B2 (en) 2009-03-13 2015-06-29 Treatment of diseases related to hyperactivity of the complement system
US15/720,933 US10940186B2 (en) 2009-03-13 2017-09-29 Treatment of diseases related to hyperactivity of the complement system
US17/171,524 US20210268076A1 (en) 2009-03-13 2021-02-09 Treatment of Diseases Related to Hyperactivity of the Complement System

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014203188A3 (fr) * 2013-06-19 2015-04-23 Glaxosmithkline Intellectual Property (No.2) Limited Nouveau dosage
WO2017194912A1 (fr) 2016-05-09 2017-11-16 Cambridge Enterprise Limited Traitement de troubles médiés par le complément
EP3262066B1 (fr) 2015-10-28 2018-02-07 Syncona Investment Management Limited Thérapie génique
WO2018170152A1 (fr) * 2017-03-14 2018-09-20 Gemini Therapeutics Facteur du complément mature i recombinant
US10155983B2 (en) 2014-03-31 2018-12-18 Machaon Diagnostics, Inc. Method of diagnosis of complement-mediated thrombotic microangiopathies
US10940186B2 (en) 2009-03-13 2021-03-09 Cambridge Enterprise Limited Treatment of diseases related to hyperactivity of the complement system

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2017210042B2 (en) 2016-01-20 2021-01-21 396419 B.C. Ltd. Compositions and methods for inhibiting Factor D
WO2018136827A1 (fr) 2017-01-20 2018-07-26 Vitrisa Therapeutics, Inc. Compositions à boucle en épingle à cheveux et procédés pour inhiber le facteur d

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0742235B2 (ja) 1985-11-08 1995-05-10 三共株式会社 自己免疫性疾病の予防・治療剤
DK570485D0 (da) 1985-12-10 1985-12-10 Novo Industri As Humant conglutinin
US5256642A (en) * 1988-04-01 1993-10-26 The Johns Hopkins University Compositions of soluble complement receptor 1 (CR1) and a thrombolytic agent, and the methods of use thereof
US5221616A (en) * 1988-07-15 1993-06-22 Quidel Corporation Prevention of spontaneous complement activation in mammalian biological fluids
DK708488D0 (da) * 1988-12-20 1988-12-20 Nordisk Gentofte Faktor i praeparat
US7795218B2 (en) * 2001-04-12 2010-09-14 Bioaxone Therapeutique Inc. ADP-ribosyl transferase fusion variant proteins
US8088579B2 (en) * 2005-02-14 2012-01-03 University Of Iowa Research Foundation Complement factor H for diagnosis of age-related macular degeneration
EP1928483B1 (fr) * 2005-09-19 2016-12-28 CSL Behring GmbH Facteur h pour le traitement de la fibrose tubulo-interstitialle et de l'insuffisance rénale progressive
US8168584B2 (en) 2005-10-08 2012-05-01 Potentia Pharmaceuticals, Inc. Methods of treating age-related macular degeneration by compstatin and analogs thereof
FR2894145B1 (fr) * 2005-12-07 2008-10-17 Lab Francais Du Fractionnement Utilisation de facteur h du complement a titre de medicament
AT503491B1 (de) 2006-03-03 2008-03-15 Seibt Kristl & Co Gmbh Vorrichtung zur erzeugung von drehschwingungen
SI2044111T1 (sl) * 2006-06-21 2015-02-27 Musc Foundation For Research Development Ciljanje komplementa faktorja H za zdravljenje bolezni
US8192742B2 (en) * 2007-03-23 2012-06-05 NovelMed Therapeutics Method of inhibiting complement activation with human anti-factor C3 antibodies and use thereof
US20110092446A1 (en) * 2007-07-20 2011-04-21 Cedric Francois Compositions and methods for treatment of trauma
KR101190594B1 (ko) * 2008-02-14 2012-10-15 재단법인 목암생명공학연구소 유전자 치료용 코딩 서열의 발현에 적합한 발현 벡터
GB0904427D0 (en) 2009-03-13 2009-04-29 Lachmann Peter Treatment of diseases related to hyperactivity of the complement system

Non-Patent Citations (35)

* Cited by examiner, † Cited by third party
Title
"Lachmann PJ (1979) An evolutionary view of the complement system", BEHRING INST MITT, no. 63, 1979, pages 25 - 37
ALSO KL; KIHL J: "Pasteurisation of a factor I (C3b inactivator) concentrate from human plasma", VOX SANG, vol. 5, no. 7, 1989, pages 240 - 2
BURNOUF T; RADOSOVICH M: "Nanofiltration of plasma-derived biopharmaceutical products", HAEMOPHILIA, 2003, pages 24 - 37
DENTCHEV, T.; MILAM, A. H.; LEE, V. M.; TROJANOWSKI, J. Q.; DUNAIEF, J. L.: "Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas", MOL. VIS., vol. 9, 2003, pages 184 - 190, XP003001744
DING, J.-D.; LIN, J.; MACE, B. E.; HERRMANN, R.; SULLIVAN, P.; RICKMAN, C. B.: "Targeted age-related macular degeneration with Alzheimer's disease based immunotherapies: anti-amyloid-? antibody attenuates pathologies in an age-related macular degeneration mouse model", VIS. RES., vol. 48, 2008, pages 339 - 345, XP022452227, DOI: doi:10.1016/j.visres.2007.07.025
GIANAZZA E; ARNAUD P: "A general method for fractionation of plasma proteins. Dye-ligand affinity chromatography on immobilized Cibacron blue F3-GA", BIOCHEM J, vol. 201, 1982, pages 129 - 36, XP008067795
GLOVER GI ET AL., MOL IMMUNOL., vol. 25, 1988, pages 1261 - 7
GOICOECHEA DE JORGE E; HARRIS CL; ESPARZA-GORDILLO J; CARRERAS L; ARRANZ EA; GARRIDO CA; LÓPEZ-TRASCASA M; SÁNCHEZ-CORRAL P; MOR: "MUTATIONS IN FACTOR B THAT INCREASE ITS FUNCTION AS A C3-CONVERTASE PREDISPOSE TO AHUS", PROC NATL ACAD SCI U S A, vol. 104, no. 1, 2007, pages 240 - 245
JANSSEN BJC ET AL., NATURE, vol. 444, 2006, pages 213 - 6
JING H ET AL., J MOL BIOL., vol. 282, 1998, pages 1061 - 81
KAVANAGH D; RICHARDS A; NORIS M; HAUHART R; LISZEWSKI MK; KARPMAN D; GOODSHIP JA; FREMEAUX-BACCHI V; REMUZZI G; GOODSHIP TH: "Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome", MOL IMMUNOL., 2008, pages 95 - 105
LACHMANN ET AL., IMMUNOLOGY, vol. 41, no. 3, 1980, pages 503 - 515
LACHMANN PJ; HALBWACHS L: "The influence ofC3b inactivator (KAF) concentration on the ability of serum to support complement activation", CLIN EXP IMMUNOL, 1975, pages 21109
LACHMANN, P.J.; ASTON, W.P.; NICOL, P.A.E., IMMUNOCHEMISTRY, vol. 10, 1973, pages 695
LACHMANN, P.J.; MULLER-EBERHARD, H.J., J IMMUNOL., vol. 100, 1968, pages 691
LACHMANN; MULLER-EBERHARD, J IMMUNOL., vol. 100, 1968, pages 691
LACHMANN; NICOL; ASTON, IMMUNOCHEM, vol. 10, 1973, pages 695
LAMBERT ET AL.: "Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease", NAT. GENET., 6 September 2009 (2009-09-06)
PICKERING MC; JORGE EG; MARTINEZ-BARRICARTE R; RECALDE S; GARCIA-LAVANA A; ROSE KL; MOSS J; WAPORT MJ; COOK HT; CÓRDOBA SR: "Spontaneous hemolylic uremic syndrome triggered by complement factor H lacking surface recognition domains", J EXP MED., vol. 204, no. 6, 2007, pages 1249 - 56
RANA JS; BOEKHOLDT SM; RIDKER PM; JUKEMA JW; LUBEN R; BINGHAM SA; DAY NE; WAREHAM NJ; KASTELEIN JJ; KHAW KTJ: "Differential leucocyte count and the risk offuture coronary artery disease in healthy men and women: the EPIC-Norfolk Prospective Population", STUDY INTERN MED., vol. 262, no. 6, 2007, pages 678 - 89
REMINGTON: "The Science and Practice of Pharmacy", 2005
RICHARDS A; KAVANAGH D; ATKINSON JP: "Inherited Complement Regulatory Protein Deficiency Predisposes to Human Disease in Acute Injury and Chronic Inflammatory States. The Examples of Vascular Damage in Atypical Hemolytic Uremic Syndrome and Debris Accumulation in Age-Related Macular Degeneration", ADV IMMUNOL., vol. 96, 2007, pages 141 - 77
ROSE KL; PAIXAO-CAVALCANTE D; FISH J; MANDERSON AP; MALIK TH; BYGRAVE AE; LIN T; SACKS SH; WALPORT MJ; COOK HT: "Factor I is requiredfor the development of membranoproliferative glomerulonephritis in factor H-deficient mice", J CLIN INVEST., vol. 118, no. 2, February 2008 (2008-02-01), pages 608 - 18
See also references of EP2405931A2
SORENSEN H; DISSING J: "Association between the C3F gene and atherosclerotic vascular diseases", HUM HERED, vol. 25, no. 4, 1975, pages 279 - 83
ULLMAN CG; CHAMBERLAIN D; ANSARI A; EMERY VC; HARIS PI; SIM RB; PERKINS SJ: "Human complement factor I: its expression by insect cells and its biochemical and structural characterisation", MOL IMMUNOL, vol. 35, 1998, pages 503 - 12, XP029994245, DOI: doi:10.1016/S0161-5890(98)00052-2
WANG, J.; OHNO-MATSUI, K.; YOSHIDA, T.; KOJIMA, A.; SHIMADA, N.; NAKAHAMA, K.; SAFRANOVA, O.; IWATA, N.; SAIDO, T. C.; MOCHIZUKI,: "Altered function of Factor I caused by amyloid P: implication for pathogenesis of age-related macular degeneration from drusen", J. IMMUNOL., vol. 181, 2008, pages 712 - 720, XP002608699
WANG, J.; OHNO-MATSUI, K.; YOSHIDA, T.; SHIMADA, N.; ICHINOSE, S.; SATO, T.; MOCHIZUKI, M.; MORITA, I.: "Amyloid-? up-regulates complement Factor B in retinal pigment epithelial cells through cytokines released from recruited macrophages/microglia: another mechanism of complement activation in age-related macular degeneration", J. CEL. PHYSIOL., vol. 220, 2009, pages 119 - 128
WILLIAMSON LM; ALLAIN JP: "Virally inactivated fresh frozen plasma", VOX SANG., vol. 69, 1995, pages 159 - 65
WONG MJ; GOLDBERGER G; ISENMAN DE; MINTA JO: "Processing of human factor I in COS-1 cells co-transfected with factor I and paired basic amino acid cleaving enzyme (PACE) cDNA", MOL IMMUNOL, vol. 32, 1995, pages 379 - 87, XP002350310, DOI: doi:10.1016/0161-5890(94)00151-P
XIA Y; VETVICKA V; YAN J; HANIKÝROVÁ M; MAYADAS T; ROSS GD: "The beta-glucan-binding lectin site of mouse CR3 (CD11b/CD18) and its function in generating a primed state of the receptor that mediates cytotoxic activation in response to iC3b-opsonized target cells", J IMMUNOL, vol. 162, no. 4, 1999, pages 2281 - 90, XP008043583
YATES JR; SEPP T; MATHARU BK; KHAN JC; THURLBY DA; SHAHID H; CLAYTON DG; HAYWARD C; MORGAN J; WRIGHT AF: "Complement C3 variant and the risk of age-related macular degeneration", N ENGL J MED., vol. 357, 2007, pages 553 - 61
YOSHIDA, T.; OHNO-MATSUI, K.; ICHINOSE, S.; SATO, T.; IWATA, N.; SAIDO, T. C.; HISATOMI, T.; MOCHIZUKI, M.; MORITA, I.: "The potential role of amyloid beta in the pathogenesis of age-related macular degeneration", J. CLIN. INVEST., vol. 115, no. 10, 2005, pages 2793 - 2800, XP009111916, DOI: doi:10.1172/JCI24635
ZETTERBERG, M.; LANDGREN, S.; ANDERSSON, M. E.; PALMÉR, M. S.; GUSTAFSON, D. R.; SKOOG, I.; MINTHON, L.; THELLE, D. S.; WALLIN, A: "Association of complement Factor H Y402H gene polymorphism with Alzheimer's disease", AMER. J. MED. GENET. PAART B (NEUROPSYCHIATRIC GENET.), vol. 147B, 2008, pages 720 - 726
ZIEGLER JB; ALPER CA; ROSEN FS; LACHMANN PJ; SHERINGTON L: "Restoration by purified C3b inactivator of complement-mediated function in vivo in a patient with C3b inactivator deficiency", J CLIN INVEST, vol. 55, 1975, pages 668

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